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Searching for an alternative to doxycycline for Lyme disease, researchers screen 500 approved compounds and find piperacillin can kill B. burgdorefi in mice by disrupting peptidoglycan synthesis without impacting the gut microbiome.
A high-resolution screen identifies a preexisting beta-lactam that specifically treats Lyme disease in mice by Maegan E. Gabby, Abey Bandara, L. M. Outrata, Osamudiamen Ebohon, Saadman S. Ahmad, Jules M. Dressler, Mecaila E. McClune, Rebecca N. Trimble, Lainey Mullen, and Brandon L. Jutras, April 23, 2025, Science Translational Medicine, Vol 17, Issue 795
DOI: 10.1126/scitranslmed.adr9091
Editor’s summary
As the tick vector for Borrelia burgdorferi expands its range, more individuals are at increased risk of both acute Lyme disease (caused by B. burgdorferi infection) and postacute sequelae after Lyme disease. In a pair of papers, Gabby et al. and McClune et al. expand our knowledge of B. burgdorferi with the goal of combatting Lyme disease. Gabby et al. posited that antibiotics other than high-dose doxycycline may be able to specifically kill B. burgdorferi. They found that a beta-lactam, piperacillin, could eliminate B. burgdorferi in vitro and in mice (notably without affecting the microbiome) and provided the mechanistic basis of this activity. McClune et al. investigated how the B. burgdorferi peptidoglycan (PGBb) may drive long-term consequences of Lyme disease. They observed that a particular form of PGBb could persist in the mouse liver for much longer than others, or even peptidoglycan from different bacteria, suggesting that PGBb could serve as a source of continuous antigen, thereby driving inflammation. Altogether, these studies highlight the need to clear B. burgdorferi to avoid persistent PGBb and provide another antibiotic that may be able to do so. —Courtney Malo
Abstract
Lyme disease, caused by Borrelia burgdorferi in the United States, is an escalating human health problem that can cause severe disease if not properly treated. Doxycycline is the primary treatment option for Lyme disease; however, several concerns are associated with high-dose doxycycline treatment. For example, doxycycline is a broad-spectrum antibiotic and kills beneficial bacteria. Doxycycline is also known to produce unwanted off-target effects in eukaryotic cells. Some at-risk populations such as young children cannot be prescribed doxycycline, and in addition to these shortcomings, the treatment appears to fail in 10 to 20% of cases. We reasoned that safe, alternative therapies may currently exist but have not yet been found because of the challenges associated with drug screening approaches. We screened nearly 500 US Food and Drug Administration–approved compounds using an array of physiological, cellular, and molecular techniques. Top-performing candidates were counter screened to identify compounds that did not affect other bacterial phyla. Piperacillin emerged as a compound that eradicated B. burgdorferi at low-nanomolar concentrations by specifically interfering with the unusual, multizonal peptidoglycan synthesis pattern common to the Borrelia clade. Mechanistic in vitro studies identified the cellular target of piperacillin in B. burgdorferi and produced key insights that may explain both the specificity and efficacy of the compound. Further, in vivo studies using an experimental mouse infection model demonstrated that piperacillin treated animals at a 100-fold lower dose than the effective dose of doxycycline without affecting the murine microbiome. Our findings suggest that piperacillin may offer clinicians another therapeutic option for Lyme disease.
Related Research Article
By Mecaila E. McClune, Osamudiamen Ebohon, Jules M. Dressler, et al. Science Translational Medicine 23 Apr 2025
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